The primary purpose of this project is to study the long-term effect of resveratrol, the antioxidant compound found in red wine, on age-related hearing loss. Presbyacusis is a progressive deterioration of hearing loss associated with aging and is the most common cause of adult auditory deficiency in the United States. 23% of the population between ages 65 and 75 years and 40% of the population older than 75 years are affected. Compelling evidence suggests that aging-related diseases progress due to the accumulation of reactive oxygen species (ROS). ROS are primarily produced in vivo during mitochondrial respiration, the process that provides energy to cells. ROS cause damage to mitochondrial DNA (mtDNA), resulting in the production of specific mtDNA deletions and mutations; these produce bioenergetically deficient cells. Ultimately, this persistent attack of ROS on mitochondrial and cellular structures results in cell death, tissue damage and hearing loss. Isolated grape constituents such as resveratrol, catechins and flavanols are noted for their antioxidant and anti-inflammatory properties and their potential for preventing cancer and heart disease. Resveratrol is 20 times more potent than Vitamin C and has been found to be more effective at preventing oxidative DNA damage than any other antioxidant. By decreasing the activity of Complex 3 of mitochondrial oxidative phosphorylation chain, it opposes the production of ROS and scavenges them. This protects against age-related nerve changes. Preliminary studies conducted in our laboratory have shown that resveratrol protects against noise-induced hearing loss as well. This project will study the effects of resveratrol on mitochondrial and auditory functions. We hypothesize that aged animals that have been treated with resveratrol will have improved auditory sensitivity and mitochondrial function and reduced inner ear hair cell loss compared to control animals. The differences in auditory sensitivity will be studied by auditory brainstem response measurements. The differences in mitochondrial function will be studied by measuring the mitochondrial membrane potentials, mitochondrial respiratory enzyme level (complex 1) and mtDNA deletions. We will also study the expression of 5-lipoxygenase, cyclooxygenase 1 and 2 as indirect measures of ROS generation. These studies will provide the foundation for developing clinical studies to investigate the use of antioxidants and mitochondrial-function enhancing nutritional supplements to attenuate auditory deterioration in patients with presbyacusis. Furthermore, these data will provide novel strategies to impart greater wellness in the elderly population and perhaps have a positive effect on health care expenses.